(1) Field of the Invention
The present invention relates generally to the field of biodegradable polymers for the controlled release of biologically active agents therefrom. More particularly, the present invention relates to a process for preparing hydrophobic biodegradable polymers of controlled size in which there is a physical interaction with the protein or polypeptide incorporated therein. Such an interaction promotes incorporation of the protein or polypeptide into the polymer matrix and allows for protection and controlled release of the protein or polypeptide from the polymer.
(2) Background of the Prior Art
A wide variety of microencapsulation drug delivery systems have been developed heretofore for the rate controlled release of therapeutic agents or other agents. For instance, considerable research has been devoted to incorporating therapeutic agents into polyesters such as poly-.epsilon.-caprolactone), poly(.epsilon.-caprolactone-Co-DL-lactic acid), poly(DL-lactic acid), poly(DL-lactic acid-Co-glycolic acid) and poly(.epsilon.-caprolactone-Co-glycolic acid) in which release was diffusion controlled. See, for example, Pitt, C. G., Gratzl, M. M., Jeffcoat, A. R., Zweidinger, R., Schindler, A., "Sustained Drug Delivery Systems. II. Factors Affecting Release Rates from Poly(.epsilon.-caprolactone) and Related Biodegradable Polyesters", J. Pharm. Sci., 68, 1534 (1979). These systems were fabricated as films and capsules and the results suggest that the devices can be prepared to erode after release of the drug is essentially complete. Degradation of the polyesters has been reported to proceed by random hydrolytic cleavage of ester linkages by an autocatalytic process with the rate of chain cleavage being influenced by chemical and morphological factors.
Sustained release systems of antimalarial agents and sulfadiazine in glycolic-lactic acid copolymers have also been reported. Wise, D. L., Gesser, J. D., McCormick, G. J., "Sustained Release of a Dual Anti-malarial System", J. Pharm. Pharmacol., 31, 201 (1979). Wise, D. L., McCormick, G. J., Willett, G. P., Anderson, L. C., Howes, J. F., J. Pharm. Pharmacol., 30, 686 (1978). Methods reported by the foregoing investigators involved dissolving the agents in a suitable solvent and either spray drying or casting films according to usual methods and evaporating the solvent. Various narcotic antagonists and steroids have been incorporated in films and implanted in rats (e.g., see Woodland, J. H. R., Yolles, S., Blake, D. A., Helrich, M., Meyer, F. J., "Long-Acting Delivery Systems for Narcotic Antagonists: I", J. Med. Chem., 16, 897 (1973), Jackanicz, T. M., Nash, H. A., Wise, D. L., Gregory, J. B., "Polylactic Acid as a Biodegradable Carrier for Contraceptive Steroids", Contraception, 8, 227 (1973). Anderson, L. C., Wise, D. L., Howes J. F., "An Injectable Sustained Release Fertility Control System", Contraception, 13, 375 (1976) and incorporated into particles injected subcutaneously [Yolles, S., "Time-Release Depot for Anticancer Drugs: Release of Drugs Covalently Bonded to Polymers", J. Parent. Drug Assoc., 32, 188(1978)]. The release of a number of anti-tumor agents has been evaluated in implantable systems as reported in [Yolles, S., "Time Release Depot for Anticancer Drugs: Release of Drugs Covalently Bonded to Polymers", J. Parent. Drug Assoc., 32, 188 (1978)], and the antibiotic Mitomycin C has been encapsulated in microspherical carriers of gelatin and administered intravenously [Yoshioka, T., Hashida, M., Muranishi, S., and Sezaki, H., "Specific Delivery of Mitomycin C. to Liver, Spleen and Lung: Nano- and Microspherical Carriers of Gelatin", Intern. J. Pharm., 81, 131 (1981)] and the effect of size on in vivo distribution and the potential for antibiotic targeting was discussed. The size distribution of the microspheres (i.e., 5 to 30 .mu.m) reported in the last mentioned publication was very broad, especially for intravenous administration. Recently the in-vitro release of local anesthetics from polylactic acid spheres prepared by a solvent evaporation process has, likewise, been reported [Wakiyama, N., Kaxuhiko, J., Nakano, M., "Influence of Physicochemical Properties of Polylactic Acid on the Characteristics and In Vitro Release Patterns of Polylactic Acid Microspheres Containing Local Anesthetics", Chem. Pharm. Bull., 30, 2621 (1982)]. The patterns of release from these polylactic acid spheres were characterized by the various degrees of degradation of the polymer as well as solubilities of loaded drugs, although no attempt was apparently made to evaluate this parameter. Additionally, it is apparent that the solubility of the drug played an important role in the rate and extent of release. Scanning electron photomicrographs also revealed varying degrees of erosion and deformation of the spheres after release.
It will be seen from the foregoing that while the controlled release delivery of pharmaceuticals or other agents from heretofore described polymeric systems has been principally limited to oral, topical or implantable systems in which the considerations relative to pore size and/or cell size within the carrier matrix as well as the overall dimensions of the microspheres to be administered along with the rate of release and the relative absorption rate from a bioavailability standpoint are distinctly different from the evaluation parameters involved in the utilization of these microsphere delivery systems for parenteral, i.e., intravenous, intraarterial, intramuscular, subcutaneous, intraocular or inhalation administration routes to which the present invention is particularly applicable.
For instance, U.S. Pat. No. 4,818,542 describes a controlled release drug delivery system comprised of a spherical microprocess polymeric network of interconnecting channels.
Further, the use of proteins and peptides as therapeutic agents has been recognized and their position within the pharmaceutical armamentarium is growing due to their increasing availability. This availability is primarily due to recent advances in genetic engineering and biotechnology. Unfortunately, the use of proteinaceous drugs by conventional routes of administration is generally hampered by a variety of delivery problems. Nonparenteral routes of administration, i.e., oral and percutaneous, are inefficient primarily due to poor absorption of proteinaceous drugs into the bloodstream and degradation of such drugs in the gastrointestinal tract. Rapid proteolytic inactivation of the proteinaceous drug also occurs when the drug is administered parenterally thus decreasing its bioavailability. In addition, when administered by the parenteral route, the host's immune system is activated thereby potentially setting off a series of undesirable immune reactions.
In view of the foregoing, considerable effort has been devoted to developing alternative systems for parenteral delivery of peptides and proteins to obviate the problems associated with prior art administration techniques. For instance, implantable devices have been cast or molded from poly-(hydroxy-ethyl)methacrylate, polyvinyl alcohol, ethylene-vinylacetate copolymer (EVA) and silicone elastomer. Macromolecular drugs have been embedded in those devices. A typical method of preparation involves suspending a powder of a macromolecular drug such as a solid protein or peptide in a solution containing the polymer. The entire composition is then case or molded into the desired size and shape either by evaporating the solvent or by vulcanization. A sustained release of macromolecules from these devices has been demonstrated. The simplicity of the foregoing prior art method is its primary advantage.
To avoid the foregoing difficulties, U.S. Pat. No. 4,741,872 discloses a method for preparing biodegradable microspheres having a three-dimensional network in which biologically active macromolecular agents are physically entrapped therein.
A number of other types of protein/polymer systems are known in the art. For instance, U.S. Pat. Nos. 3,843,446, 3,977,941 and 4,601,981 discloses the preparation of enzymatically active protein-enzyme complex membrane by treating another protein membrane with an aqueous solution of an enzyme. The membranes are used to effect enzymatic reactions.
U.S. Pat. No. 3,972,776 discloses the preparation of enzymatically active protein-whole microbial cell complex membranes suitable for effecting enzymatic reactions by forming a dispersion containing synthetic or natural protein macromolecules and whole microbial cells, casting a membrane from the dispersion and drying the membrane. The membranes may also be formed by electro-codeposition from a dispersion containing the macromolecular and cells.
U.S. Pat. No. 4,758,342 relates to a hyperfiltration membrane containing a supporting layer and a separation layer.
U.S. Pat. Nos. 4,494,944 and 4,557,855 disclose a surface active agent comprised of lignin sulfonic acids, and optionally, an alkylaryl sulfonic free acid with at least ten carbon atoms and eight polypeptides having a molecular weight of about 2,500 to about 15,000.
U.S. Pat. Nos. 4,585,787 and 4,591,501 disclose a flexible continuous film which is comprised of a physical admixture of a polypeptide, a plasticizer and a film-forming flexible polymer, when the film is moistened, the polypeptide exudes therefrom.
U.S. Pat. No. 4,873,033 relates to a hyperfiltration membrane containing a supporting layer and a separation layer. The separation layer consists of a crosslinked monomolecular film of molecules, the molecules of the separation layer in the uncrosslinked state being surfactants or surfactant-like lipoids containing at least one hydrophobic chain and at least one hydrophilic group. The surfactant-like lipoid molecules are spread out under a certain spreading pressure or occupy an average space over the surface of an aqueous solution or at the interface between an aqueous solution and a liquid immersible therewith.
U.S. Pat. No. 4,897,444 relates to an immobilized fluorogenic substrate. The substrate has the structure EQU R.sub.1 --NH--R.sub.4 --R.sub.2 --R.sub.3
wherein R.sub.1 represents an enzyme-specific oligopeptide, R.sub.2 represents a spacer group which is a methylene-carboxyloxy, a methylene carboxamido or a methylenesulfonamido group attached to a polymethylene chain which itself has a functional group suitable for coupling with a polymer; R.sub.3 represents a biologically inert polymer; and R.sub.4 represents a fluorogenic moiety.
GB 2 207 050 discloses a composition comprising an aqueous solution of a drug and a glucose polymer mixture which includes at least 50% by weight of glucose polymers of D.P. greater than 12. The composition is introduced into the peritoneal cavity. The glucose polymers act as osmotic agents during peritoneal dialysis.
EP 0 354 714 discloses a pharmaceutical composition for affecting tissue redistribution of bioactive peptides and proteins which are normally bound to glycoaminoglycans, and for mimicking the action of glycoaminoglycans in biological interactions. The composition comprises a pharmaceutically acceptable polymeric compound having monomeric units and a molecular weight between 1,000 and 20,000 Daltons, wherein each monomeric unit contains between three and about 10 aromatic rings.
EP 0 187 547 relates to polymeric drugs comprising an inert synthetic polymeric carrier covalently attached to low molecular weight bioactive molecules. Drug delivery is somewhat targeted because uptake is restricted to cells capable of a substrate selective mechanism known as pinocytosis.
In spite of the numerous teachings of the prior art, the prior art drug delivery systems still have some significant disadvantages and commercialization has been difficult to achieve especially with respect to sufficient drug loading, reproducibility of product specifications and scale-up.